1. RESORCE: A Phase III Trial of Second-Line Regorafenib for HCC
2:1
Eligibility (n = 573)
Patients with HCC
Progression on sorafenib
Child-Pugh A liver function
Regorafenib 160 mg/d
(n = 379) R
Placebo
(n = 194)
Outcome
Regorafenib
(n = 379)
Placebo
(n = 194) HR
p-value
Median OS
10.6 mo
7.8 mo
0.63
<0.0001
Median PFS
3.1 mo
1.5 mo
0.46
Bruix J et al. Lancet 2017;389(10064):56-66.

2. Phase III Trials of Sorafenib in HCC
SHARP trial1
Sorafenib
(n = 299)
Placebo
(n = 303) HR
p-value
Median OS
10.7 mo
7.9 mo
0.69
<0.001
Asia-Pacific trial2
(n = 150)
(n = 76)
6.5 mo
4.2 mo
0.68
0.014
1 Llovet JM et al. N Engl J Med 2008;359(4):378-90;
2 Cheng AL et al. Lancet Oncol 2009;10(1):25-34.

3. RESORCE: A Phase III Trial of Second-Line Regorafenib for HCC
2:1
Eligibility (n = 573)
Patients with HCC
Progression on sorafenib
Child-Pugh A liver function
Regorafenib 160 mg/d
(n = 379) R
Placebo
(n = 194)
Outcome
Regorafenib
(n = 379)
Placebo
(n = 194) HR
p-value
Median OS
10.6 mo
7.8 mo
0.63
<0.0001
Almost half of the regorafenib group (184 [49%] of 374) received the full protocol dose (160 mg/day) with no reductions.
Bruix J et al. Lancet 2017;389(10064):56-66.

4. Lenvatinib 12 mg (or 8 mg) QD (oral) Sorafenib 400 mg BID (oral)
Study 304 (REFLECT): A Phase III Trial of First-Line Lenvatinib or Sorafenib for HCC
Eligibility (n = 954)
Patients with unresectable HCC
BCLC Stage B or C
Child-Pugh A liver function
ECOG PS 0-1
1:1
Lenvatinib 12 mg (or 8 mg) QD (oral)
(n = 478) R
Sorafenib 400 mg BID (oral)
(n = 476)
Outcome
Lenvatinib
(n = 478)
Sorafenib
(n = 476) HR
p-value
Median OS
13.6 mo
12.3 mo
0.92 —
Median TTP
8.9 mo
3.7 mo
0.63
<
ORR
24% 9%
Subsequent to this interview, these data were presented at ASCO 2017.
Cheng AL et al. Proc ASCO 2017;Abstract 4001.

5. RESORCE: A Phase III Trial of Second-Line Regorafenib for HCC
2:1
Eligibility (n = 573)
Patients with HCC
Progression on sorafenib
Child-Pugh A liver function
Regorafenib 160 mg/d
(n = 379) R
Placebo
(n = 194)
Almost half of the regorafenib group (184 [49%] of 374) received the full protocol dose (160 mg/day) with no reductions.
Drug-related adverse events led to interruptions or dose reductions in 202 (54%) patients in the regorafenib group.
Bruix J et al. Lancet 2017;389(10064):56-66.

6. RESORCE Phase III Trial: Select Adverse Events
Regorafenib (n = 374)
Placebo (n = 193)
All
Grade 3/4
Hand-foot skin reaction
53%
13% 8% 1%
Diarrhea
41% 3%
15% 0%
Fatigue
40% 9%
32% 5%
Hypertension
31% 6%
Increased blood bilirubin
29%
10%
18%
11%
Increased AST
25%
20%
Ascites
16% 4%
Increased ALT
Bruix J et al. Lancet 2017;389(10064):56-66.

7. CheckMate 040: Phase I/II Trial Design
Patients with advanced HCC
Dose escalation (n = 48)
3 + 3 design
Dose expansion (n = 214)
3 mg/kg
n = 6
n = 9
n = 10
n = 10
n = 13
Sorafenib untreated or intolerant (n = 56)
Without viral hepatitis
0.1 mg/kg (n = 1)
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 3)
3.0 mg/kg (n = 3)
10 mg/kg (n = 13)
Sorafenib progressor (n = 57)
HCV infected
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 4)
3.0 mg/kg (n = 3)
HCV infected (n = 50)
HBV infected
0.1 mg/kg (n = 5)
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 3)
3.0 mg/kg (n = 4)
HBV infected (n = 51)
El-Khoueiry AB et al. Lancet 2017;389(10088):

8. CheckMate 040: Response and Safety
During dose-escalation phase (n = 48):
Nivolumab showed a manageable safety profile, including acceptable tolerability.
46 (96%) discontinued treatment
Incidence of treatment-related adverse events (AEs) did not seem to be associated with dose; no maximum tolerated dose was reached.
12 (25%) had Grade 3/4 treatment-related AEs.
30 (63%) died (not determined to be related to nivolumab).
Nivolumab 3 mg/kg was chosen for dose expansion.
El-Khoueiry AB et al. Lancet 2017;389(10088):

9. CheckMate 040: Phase I/II Trial Design
Dose escalation (n = 48)
3 + 3 design
Dose expansion (n = 214)
3 mg/kg
n = 6
n = 9
n = 10
n = 10
n = 13
Sorafenib untreated or intolerant (n = 56)
Without viral hepatitis
0.1 mg/kg (n = 1)
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 3)
3.0 mg/kg (n = 3)
10 mg/kg (n = 13)
Sorafenib progressor (n = 57)
HCV infected
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 4)
3.0 mg/kg (n = 3)
HCV infected (n = 50)
HBV infected
0.1 mg/kg (n = 5)
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 3)
3.0 mg/kg (n = 4)
HBV infected (n = 51)
With nivolumab at 3 mg/kg:
ORR (dose-expansion phase) = 42/214 (20%)
El-Khoueiry AB et al. Lancet 2017;389(10088):

10. CheckMate 040: Survival Results
Outcomes
Dose escalation
(n = 48)*
Dose expansion
(n = 214)†
Median OS
15 mo NR
6-month OS
66%
83%
9-month OS
74%
Median PFS
3.4 mo
4.0 mo
6-month PFS
Not reported
37%
9-month PFS
28%
* 37/48 (77%) had previously received sorafenib
† 145/214 (68%) of patients had previously received sorafenib
NR = not reached
Median OS – uninfected, prior sorafenib in dose-expansion phase (n = 57) = 13.2 mo
El-Khoueiry AB et al. Lancet 2017;389(10088):

11. CheckMate 040: Treatment Outcomes
Nivolumab
Dose escalation
(n = 48)
Dose expansion
(n = 214)
ORR
7 (15%)
42 (20%)
Median DoR
17 mo
9.9 mo
DCR
28 (58%)
138 (64%)
9-month OS
66%
74%
El-Khoueiry AB et al. Lancet 2017;389(10088):

12. Select Ongoing Trials of Immune Checkpoint Inhibitors for Patients with Advanced HCC
Trial name/identifier N
Phase
Setting
Treatment arms
CheckMate 459 (NCT )
726
III
First line
Nivolumab
Sorafenib
CheckMate (NCT )
620
I/II
2 parts*/5 cohorts (C1- 5)
Uninfected
HCV infected
HBV infected
Advanced HCC
Child-Pugh B
Nivo at different doses (C1-3)
Nivo at a specific dose (C1-3)
1L Nivo vs sorafenib (C4)
Nivo vs ipilimumab (C4)
Nivo (C5)
16-C-0135 (NCT ) 90
Advanced BCLC Stage B/C
Intra/extrahepatic cholangiocarcinoma
Tremelimumab + durvalumab +/- (TACE or RFA or cryoablation) (C1)
* The 2 parts are dose escalation and dose expansion.
Clinicaltrials.gov (Accessed July 2017).

13. Phase II Trial of Tremelimumab Monotherapy in HCC with Chronic Hepatitis C
Outcomes
n = 17
ORR
17.6%
DCR
76.4%
Time to progression
6.48 mo
Median OS
8.2 mo
Sangro B et al. J Hepatol 2013;59(1):81-8.

14. Ongoing CheckMate 040 Trial
Trial name/identifier N
Phase
Setting
Treatment arms
CheckMate 040
(NCT )
620
I/II
2 parts*/5 cohorts (C1-5)
Uninfected
HCV infected
HBV infected
Advanced HCC
Child-Pugh B
Nivo at different doses (C1-3)
Nivo at a specific dose (C1-3)
1L Nivo vs sorafenib (C4)
Nivo + ipilimumab (C4)
Nivo (C5)
* The 2 parts are dose escalation and dose expansion.
Clinicaltrials.gov (Accessed July 2017).

15. CheckMate 040: Select Adverse Events
Dose-escalation cohort
Nivolumab 3 mg/kg (n = 10)
All patients (n = 48)
All grades
Grade 3/4
Increased AST
1 (10%)
10 (21%)
5 (10%)
Increased ALT
2 (20%)
7 (15%)
3 (6%)
Increased lipase
6 (13%)
Increased amylase
9 (19%)
2 (4%)
One patient without viral hepatitis who received nivolumab 3 mg/kg discontinued due to treatment-related ALT and AST increases without concomitant changes in liver function.
El-Khoueiry AB et al. Lancet 2017;389(10088):

16. Case Discussion
A 74-year-old man presents with chronic hepatitis B with no evidence of portal hypertension or cirrhosis.
Patient has a single 6.5-cm lesion and is diagnosed with moderately differentiated HCC with microscopic vascular invasion
Patient underwent surgical liver resection
The margins were negative
Patient is placed on surveillance and is alive 4 years later with no evidence of recurrence

17. Case Discussion
A 71-year-old man with hepatitis B presents with abdominal pain and weight loss
He has elevated liver enzymes with an alpha-fetoprotein level of 1,000
Imaging revealed a heterogenously enhancing infiltrating mass of 6 cm with extension of the tumor.
He has tumor thrombosis into the right and left portal veins.

18. Case Discussion
A 71-year-old man with hepatitis B presents with abdominal pain and weight loss
He has elevated liver enzymes with an alpha-fetoprotein (AFP) level of 1,000 ng/mL
Imaging revealed a heterogenously enhancing infiltrating mass of 6 cm with extension of the tumor.
He has tumor thrombosis into the right and left portal veins.
A biopsy revealed poorly differentiated HCC and Child- Pugh A cirrhosis.
Patient is diagnosed with BCLC Stage C HCC.
Received first-line sorafenib  nivolumab for about 14 months on a trial upon progression

19. Case Discussion
A 68-year-old woman without viral hepatitis B, but with a metabolic syndrome, diabetes and steatohepatitis NASH presents with upper-quadrant pain and weight loss
Patient is diagnosed with NASH-related HCC with Child-Pugh A cirrhosis
Ultrasound revealed 2 liver masses, 4 and 6.5 cm
Received TACE with doxorubicin beads  response, but with residual disease

20. Case Discussion
A 68-year-old woman without viral hepatitis B, but with a metabolic syndrome, diabetes and steatohepatitis NASH presents with upper-quadrant pain and weight loss
Patient is diagnosed with NASH-related HCC with Child- Pugh A cirrhosis
Ultrasound revealed 2 liver masses, 4 and 6.5 cm
Received TACE with doxorubicin beads  response, but with residual disease
RFA therapy  observation for 14 months with no active disease  developed new liver lesion adjacent to treated large mass with invasion into the main portal vein  sorafenib

21. Case Discussion A 69-year-old man with a compensated HCV-cirrhosis
2012: Patient has a single HCC (6 cm), no macrovascular invasion (MVI) or extrahepatic spread (EHS) Child-Pugh A, ECOG PS 0, bilirubin level of 1 mg/dL and no portal hypertension 
Segmental resection: R0, no satellites, microvascular invasion 

22. Liver Transplantation for Small HCC in Patients with Cirrhosis
Outcomes
All pts
(n = 48)
Pts who met the Milan criteria
(n = 35)
Patients whose tumors exceeded the limits (n = 13)
4-year OS
75%
85%
50%
4-year RFS
83%
92%
59%
Overall mortality rate (n = 48) = 17%
In this group of 48 patients with early-stage tumors, tumor– node-metastasis status, the number of tumors, the serum AFP concentration, treatment received before transplantation and 10 other variables were not significantly correlated with survival.
Conclusions:
Liver transplantation is an effective treatment for small, unresectable HCC in patients with cirrhosis.
Mazzaferro V et al. N Engl J Med 1996;334(11):693-9.

23. Case Discussion A 69-year-old man with a compensated HCV-cirrhosis
2012: Patient has a single HCC (6 cm), no macrovascular invasion (MVI) or extrahepatic spread (EHS) Child-Pugh A, ECOG PS 0, bilirubin level of 1 mg/dL and no portal hypertension 
Segmental resection: R0, no satellites, microvascular invasion 

24. Case Discussion A 69-year-old man with a compensated HCV-cirrhosis
2012: Patient has a single HCC (6 cm), no macrovascular invasion (MVI) or extrahepatic spread (EHS) Child-Pugh A, ECOG PS 0, bilirubin level of 1 mg/dL and no portal hypertension 
Segmental resection: R0, no satellites, microvascular invasion 
2014: Multinodular HCC recurrence: 3 nodules (max: 4 cm). Patient has Child-Pugh A, ECOG 0, no MVI-EHS, AFP: 100 ng/mL 
Chemoembolization (TACE x 3): partial response 

25. Case Discussion A 69-year-old man with a compensated HCV-cirrhosis
2012: Patient has a single HCC (6 cm), no macrovascular invasion (MVI) or extrahepatic spread (EHS) Child-Pugh A, ECOG PS 0, bilirubin level of 1 mg/dL and no portal hypertension 
Segmental resection: R0, no satellites, microvascular invasion 
2014: Multinodular HCC recurrence: 3 nodules (max: 4 cm). Patient has Child-Pugh A, ECOG 0, no MVI-EHS, AFP: 100 ng/mL 
Chemoembolization (TACE x 3): partial response 
2016: Progression in main HCC nodule: 5 cm, satellites and branch portal vein thrombosis; Child-Pugh A, ECOG PS 1, bilirubin 1.5 mg/dL, AFP: 600 ng/mL. 

26. Case Discussion A 69-year-old man with a compensated HCV-cirrhosis
2012: Patient has a single HCC (6 cm), no macrovascular invasion (MVI) or extrahepatic spread (EHS) Child-Pugh A, ECOG PS 0, bilirubin level of 1 mg/dL and no portal hypertension 
Segmental resection: R0, no satellites, microvascular invasion 
2014: Multinodular HCC recurrence: 3 nodules (max: 4 cm). Patient has Child-Pugh A, ECOG 0, no MVI-EHS, AFP: 100 ng/mL 
Chemoembolization (TACE x 3): partial response 
2016: Progression in main HCC nodule: 5 cm, satellites and branch portal vein thrombosis; Child-Pugh A, ECOG PS 1, bilirubin 1.5 mg/dL, AFP: 600 ng/mL. 
Treatment strategy? (a) TACE; (b) Sorafenib; (c) TARE (Y-90); (d) Radiation therapy

27. BCLC Staging and Treatment Schedule
Unresectable HCC
Llovet JM et al. Nat Rev Dis Primers 2016;2:16018.

28. Intermediate – Advanced HCC: Redefining “Unresectable” HCC — Natural History (BCLC B and C)
Survival BCLC B stage (n = 370)
Survival BCLC C stage (n = 376)
Stage 0
Median survival: Placebo 15.8m
Seocalcitol 15.1m
Stage 1
Median survival: Placebo 5.7m
Seocalcitol 5.6m
Survival
Survival
Time since treatment start (months)
Time since treatment start (months)
RCT seocalcitol vs placebo (n = 746)
Courtesy of Josep M Llovet, MD, PhD

29. BCLC Staging and Treatment Schedule
Llovet JM et al. Nat Rev Dis Primers 2016;2:16018.

30. Evidence and Recommendations for HCC Therapies
Sorafenib 1
Chemoembolization
RF (<5 cm), RF/PEI (<2 cm)
Adjuvant therapy after reseaction
LDLT
Resection
OLT-Milan
Internal radiation 2
Levels of evidence
OLT-extended
Neoadjuvant therapy in waiting list
Downstaging 3
External/palliative radiation therapy C B A C B A
2 (weak)
1 (strong)
Grade of recommendation
EASL-EORTC clinical practice guidelines. J Hepatol 2012;56(4):

31. Systemic Therapies: Sorafenib
Clinical Practice Summary
Systemic therapies
Sorafenib is the standard systemic therapy for HCC. It is indicated for patients with well- preserved liver function (Child-Pugh A class) and with advanced tumors (BCLC C) or those tumors progressing upon locoregional therapies (evidence 1iA; recommendation 1A)
There are no clinical or molecular biomarkers available to identify the best responders to sorafenib (evidence 1A; recommendation 2A)
Systemic chemotherapy, tamoxifen, immunotherapy, anti-androgen and herbal drugs are not recommended for the clinical management of HCC (evidence 1-2A; recommendation 1A/B)
SHARP trial results
Median OS (N = 602):
Sorafenib = 10.7 mo
Placebo = 7.9 mo
HR = 0.69
p < 0.001
EASL-EORTC clinical practice guidelines. J Hepatol 2012;56(4):908-43;
Llovet JM et al. N Engl J Med 2008;359(4):  

32. SHARP: Subgroup Analysis
Subgroup domain
Group evaluated
Number of patients
OS (mo)
Sor PI HR
Tumor burden
MVI/EHS both absent 90 91
14.5
10.2
0.52
MVI/EHS both present
209
212
8.9
6.7
0.77
MVI absent
190
179
14.1
0.74
MVI present
108
123
8.1
4.9
0.68
EHS absent
140
153
7.9
0.55
EHS present
159
150
8.3
0.85
Performance status
ECOG PS 0
161
164
13.3
8.8
ECOG PS 1-2
138
139
5.6
0.71
Tumor stage
BCLC B 54 51
11.4
0.72
BCLC C
245
252
9.7
7.0
0.70
Prior therapy
Prior curative treatment 81 77
11.9
0.79
Prior TACE 86
9.9
0.75
MVI = microvascular invasion
Bruix J et al. J Hepatol 2012;57(4):821-9.

33. Alternative Therapies for MVI in HCC: Surgical Resection
Series
Number of patients
Survival
Predictors of outcome
Median (mo)
5 year (%) Wu
112 NA 27
Ohkubo 47 24
Tumor size 10 cm, satellites, margins
Poon 20 6
Fan 83 13 14
Adjuvant CT
108 15
Adjuvant CT, tumor size 10 cm
Pawlik
102 11 10
Fibrosis
Le Treut 26 9
Chen
438 16 12
Extent of invasion
Zhou
381
Ikai 78 22
Ascites, INR, tumor size 5 cm
Liang 86
Adjuvant treatment, grade, tumor size
Shimada 7
Ban 45
AFP <2,000, serosal invasion
Inoue 49 19 40
Kondo 48
Total bilirubin, alkaline phosphatase, extent of invasion
Ruzzenente 17
Shi
406
Retrospective Study by Roayaie et al.
N = 165
Median OS = 13.1 mo
5-year OS = 14%
Retrospective studies, underpowered; selection bias; lack of ITT analysis
Hypothesis generating
Roayaie S et al. Ann Surg Oncol 2013;20(12):  

34. Alternative Therapies for MVI in HCC: Loco-regional Therapies (TACE and Radiation Therapy)
Author
Treatment (n)
Survival
Xue, BMC Gastro 2013
TACE (923)
Meta-analysis
Gorodetski, Eur Rad 2016
TACE (95) TACE-DEB (38)
5 mo 3.3 mo
Zhu K, Radiology 2014
TACE+S (46) TACE (45)
13 mo 6 mo
Memon K, J Hep 2013
Y-90 Child-Pugh A (45)
Y-90 Child-Pugh B (28)
13.8 mo 6.5 mo
Nakazawa, BMC Gastro 2014
Sorafenib (40)
Radiation therapy (57)
4.3 mo 5.9 mo
Retrospective studies, underpowered
Selection bias; lack of ITT analysis
Hypothesis generating

35. Radioembolization 90Y for Portal Vein Invasion in HCC
Prospective/Retrospective Studies
Reporting on long-term outcome after 90Y radioembolization
Reference
Child-Pugh A
Intermediate stage
Branch PVT
Main PVT
Branch or main PVT N OS
Hilgard et al. (N = 108)
A/B 51
16.4 33 10
Salem et al. (N = 291) 48
17.3 19
16.6 16
7.7 35
10.4 B
13.5 27
6.5 30
4.5 57
5.6
Sangro et al. (N = 325) 82
18.4 44
10.7 32
9.7 76
10.2 5
3.6
Mazzaferro et al. (N = 51) 15 18 23 17 9 2 — 6 8 1
Hypothesis generating
Select ongoing large-scale randomized trials with 90Y radioembolization in HCC
Salem R et al. Hepatol 2013;58(6):  

36. Select Large-Scale Randomized Trials with 90Y Radioembolization in HCC
Trial name/identifier N
Phase
Setting
Treatment arms
PREMIERE
(NCT ) 45 II
Untreatable with RFA or surgery
Radioembolization
TACE
SORAMIC
(NCT )
529
Unresectable
RFA  Sorafenib or placebo
Sorafenib +/- SIRT
SIRveNIB
(NCT )
360
III
Locally advanced
Sorafenib
SIR-Spheres
SARAH
(NCT )
496
Advanced
STOP-HCC
(NCT )
390
Sorafenib + TheraSphere
YES-P
(NCT )
328
Advanced with portal vein thrombosis
TheraSphere
Clinicaltrials.gov (Accessed July 2017).  

37. Case Discussion A 69-year-old man with a compensated HCV-cirrhosis
2012: Patient has a single HCC (6 cm), no macrovascular invasion (MVI) or extrahepatic spread (EHS) Child-Pugh A, ECOG PS 0, bilirubin level of 1 mg/dL and no portal hypertension 
Segmental resection: R0, no satellites, microvascular invasion 
2014: Multinodular HCC recurrence: 3 nodules (max: 4 cm). Patient has Child-Pugh A, ECOG 0, no MVI-EHS, AFP: 100 ng/mL 
Chemoembolization (TACE x 3): partial response 
2016: Progression in main HCC nodule: 5 cm, satellites and branch portal vein thrombosis; Child-Pugh A, ECOG PS 1, bilirubin 1.5 mg/dL, AFP: 600 ng/mL. 
Patient received sorafenib  disease progression

38. RESORCE: A Phase III Trial of Second-Line Regorafenib for HCC
Eligibility (n = 573)
Patients with HCC
Progression on sorafenib
Child-Pugh A liver function
2:1
Regorafenib 160 mg/d
(n = 379) R
Placebo
(n = 194)
Outcome
Regorafenib
(n = 379)
Placebo
(n = 194) HR
p-value
Median OS
10.6 mo
7.8 mo
0.63
<0.0001
Bruix J et al. Lancet 2017;389(10064):56-66.

39. Molecular Therapies Tested in HCC (Phase III)
Targeted population
Phase III comparision
Adjuvant
Prevent recurrences
Sorafenib vs placebo (STORM)*
Retinoids vs placebo*
Intermediate HCC
Improve TACE
RF vs RF-Dox*
TACE +/- sorafenib*
TACE +/- brivanib*
Advanced HCC
First line
Sorafenib +/- erlotinib*
Sorafenib vs brivanib*
Sorafenib vs sunitinib*
Sorafenib vs linifanib*
Sorafenib +/- doxorubicin*
Sorafenib +/- Y90
Sorafenib vs lenvatinib
Sorafenib vs nivolumab
Second line
Brivanib vs placebo*
Everolimus vs placebo*
Ramucirumab vs placebo*
Regorafenib vs placebo
Tivantinib vs placebo
Cabozantinib vs placebo
Pembrolizumab vs placebo
* RCT halted or with unconclusive or negative results 
Courtesy of Josep M Llovet, MD, PhD

40. Molecular Therapies Tested in HCC (Phase III)
Targeted population
Phase III comparision
Adjuvant
Prevent recurrences
Sorafenib vs placebo (STORM)*
Retinoids vs placebo*
Intermediate HCC
Improve TACE
RF vs RF-Dox*
TACE +/- sorafenib*
TACE +/- brivanib*
Advanced HCC
First line
Sorafenib +/- erlotinib*
Sorafenib vs brivanib*
Sorafenib vs sunitinib*
Sorafenib vs linifanib*
Sorafenib +/- doxorubicin*
Sorafenib +/- Y90
Sorafenib vs lenvatinib
Sorafenib vs nivolumab
Second line
Brivanib vs placebo*
Everolimus vs placebo*
Ramucirumab vs placebo*
Regorafenib vs placebo
Tivantinib vs placebo
Cabozantinib vs placebo
Pembrolizumab vs placebo
* RCT halted or with unconclusive or negative results 
Courtesy of Josep M Llovet, MD, PhD

41. Reasons Why Randomized Trials are Negative in HCC
Limited understanding of molecular drivers
Lack of translation of knowledge into trial design
Two diseases: HCC and Cirrhosis
Balance between efficacy and toxicity
Sunitinib, linifanib
Difficult trial design
Noninferiority concept (brivanib, linifanib)
Surrogate endpoints of survival? TTP (contradictory data), ORR
Moving to Phase III without clear signals
Sunitinib, erlotinib
Drugs are not powerful enough
Brivanib, linifanib, erlotinib, everolimus, ramucirumab, doxorubicin
Courtesy of Josep M Llovet, MD, PhD

42. Phase II Trial of Second-Line Regorafenib
Dose
Efficacy (n = 36)
Safety (n = 36)
Event
All
Grade ≥3
160 mg PO QD (21 d on/7 d off)
DCR: 72%
HFSR
53%
14%
PR: 3%
Diarrhea 6%
SD: 69%
Fatigue
17%
Median TTP: 4.3 mo
Hypothyroidism
42% 0%
Median OS: 13.8 mo
Hypertension
36% 3%
Bruix J et al. Eur J Cancer 2013;49(16):

43. RESORCE: A Phase III Trial of Second-Line Regorafenib for HCC
Eligibility (n = 573)
Patients with HCC
Progression on sorafenib
Child-Pugh A liver function
2:1
Regorafenib 160 mg/d
(n = 379) R
Placebo
(n = 194)
Outcome
Regorafenib
(n = 379)
Placebo
(n = 194) HR
p-value
Median OS
10.6 mo
7.8 mo
0.63
<0.0001
Bruix J et al. Lancet 2017;389(10064):56-66.

44. RESORCE Phase III Trial: Select Adverse Events
Regorafenib (n = 374)
Placebo (n = 193)
All
Grade 3/4
Hand-foot skin reaction
53%
13% 8% 1%
Diarrhea
41% 3%
15% 0%
Fatigue
40% 9%
32% 5%
Hypertension
31% 6%
Bruix J et al. Lancet 2017;389(10064):56-66.

45. Case Discussion A 69-year-old man with a compensated HCV-cirrhosis
2012: Patient has a single HCC (6 cm), no macrovascular invasion (MVI) or extrahepatic spread (EHS) Child-Pugh A, ECOG PS 0, bilirubin level of 1 mg/dL and no portal hypertension 
Segmental resection: R0, no satellites, microvascular invasion 
2014: Multinodular HCC recurrence: 3 nodules (max: 4 cm). Patient has Child-Pugh A, ECOG 0, no MVI-EHS, AFP: 100 ng/mL 
Chemoembolization (TACE x 3): partial response 
2016: Progression in main HCC nodule: 5 cm, satellites and branch portal vein thrombosis; Child-Pugh A, ECOG PS 1, bilirubin 1.5 mg/dL, AFP: 600 ng/mL. 
Patient received sorafenib  disease progression

46. Lenvatinib as First-Line Therapy: Activity
Inclusion criteria
Exclusion criteria
PR (%)
SD (%)
TTP (months)
OS (months)
Lenvatinib Phase I
Advanced HCC, CP-A, B
Simultaneous cancers, ascites, effusion, brain metastases, portal vein shunt, use of CYP3A4 20 45
3.7 —
Lenvatinib Phase II
Advanced HCC, CP-A, previous 1 line of systemic treatment
32.6
45.7
7.49
13.9
Sorafenib Phase I
Advanced, biopsy- proven HCC, chemo-naïve, CP-A/B, ECOG PS 0-1
Tumor of mixed histology, pregnant or lactating, those requiring systemic anticancer therapy, biologic response modifiers
2.2
33.6
4.2
9.2
Brivanib Phase II
Advanced HCC, second-line therapy, CLIP score 3 or less, ECOG PS 0-2
Active bacterial infection, HIV, significant cardiovascular disease
4.3
41.3
2.7
9.79
Sunitinib Phase II
Advanced HCC, chemo-naïve, ECOG PS 0-1, CP <B8
Previous chemotherapy 12
42.1
2.8
5.8
CP = Child-Pugh
Courtesy of Josep M Llovet, MD, PhD

47. Lenvatinib vs Sorafenib: Adverse Events and Ongoing Trial
Lenvatinib Phase II; all grades (%)
Sorafenib SHARP trial; all grades (%)
Fatigue 54 22
Hand-foot syndrome 65 21
Anorexia 59 14
Diarrhea — 39
Hypertension 76 5
Thrombocytopenia 52
Proteinuria
Leukopenia
7.9
Subsequent to this interview, the results of the Phase III REFLECT open-label, noninferiority trial of lenvatinib vs sorafenib were presented at ASCO 2017. 
Ikeda K et al. Proc ESMO 2012;Abstract 737P; Llovet JM et al. N Engl J Med 2008; 359(4): Clinicaltrials.gov (Accessed July 2017).

48. CheckMate 040: A Phase I/II Trial of Nivolumab in Advanced HCC
Dose escalation (n = 48)
3 + 3 design
Dose expansion (n = 214)
3 mg/kg
n = 6
n = 9
n = 10
n = 10
n = 13
Sorafenib untreated or intolerant (n = 56)
Without viral hepatitis
0.1 mg/kg (n = 1)
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 3)
3.0 mg/kg (n = 3)
10 mg/kg (n = 13)
Sorafenib progressor (n = 57)
HCV infected
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 4)
3.0 mg/kg (n = 3)
HCV infected (n = 50)
HBV infected
0.1 mg/kg (n = 5)
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 3)
3.0 mg/kg (n = 4)
HBV infected (n = 51)
El-Khoueiry AB et al. Lancet 2017;389(10088):

49. CheckMate 040: A Phase I/II Trial of Nivolumab in Advanced HCC
Dose escalation (n = 48)
3 + 3 design
Dose expansion (n = 214)
3 mg/kg
n = 6
n = 9
n = 10
n = 10
n = 13
Sorafenib untreated or intolerant (n = 56)
Without viral hepatitis
0.1 mg/kg (n = 1)
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 3)
3.0 mg/kg (n = 3)
10 mg/kg (n = 13)
Sorafenib progressor (n = 57)
HCV infected
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 4)
3.0 mg/kg (n = 3)
HCV infected (n = 50)
HBV infected
0.1 mg/kg (n = 5)
0.3 mg/kg (n = 3)
1.0 mg/kg (n = 3)
3.0 mg/kg (n = 4)
HBV infected (n = 51)
Cohort N
ORR
9-month OS
Median OS
Dose-escalation cohort 48
7 (15%)
66%
15 mo
Dose-expansion cohort
214
42 (20%)
74%
Not reached
Median OS – uninfected, prior sorafenib in dose-expansion phase (n = 57) = 13.2 mo
El-Khoueiry AB et al. Lancet 2017;389(10088):

50. CheckMate 459: An Ongoing Phase III Trial
Target accrual (n = 726)
Pts with advanced HCC
Not eligible for surgical and/or locoregional therapies or
Progressive disease after surgical and/or locoregional therapies
Child-Pugh A
ECOG PS 0-1
No prior liver transplant
Nivolumab R
Sorafenib
Primary endpoints: OS and ORR
Clinicaltrials.gov (Accessed July 2017).

51. Ongoing Trials of Combinations of Immune Checkpoint Inhibitors for HCC
Trial name/identifier N
Phase
Setting
Treatment arms
16-C (NCT ) 90
I/II
Advanced BCLC Stage B/C
Intra/extra hepatic cholangiocarcinoma
Tremelimumab + durvalumab +/- (TACE or RFA or cryoablation) (C1)
CheckMate 040
(NCT )
620
2 parts*/5 cohorts (C1-5)
Uninfected
HCV infected
HBV infected
Advanced HCC
Child-Pugh B
Nivo at different doses (C1-3)
Nivo at a specific dose (C1-3)
1L Nivo vs sorafenib (C4)
Nivo + ipilimumab (C4)
Nivo (C5)
* The 2 parts are dose escalation and dose expansion.
Clinicaltrials.gov (Accessed July 2017).